The lethality of prostate cancer (PCa) is attributable to the metastatic castration resistant state (CRPC). Accordingly, an understanding of the biochemical and genetic alterations that drive metastasis and castration resistance offers the potential and promise of identifying molecular targets for therapeutic intervention. During the current SPORE funding period, we have made significant advances in the elucidation of key signaling pathways that mediate castration resistance and metastasis. To investigate the molecular underpinnings of metastasis in Aim 1 of our proposal, we will use our recently developed mouse model in which the PI3K/AKT and Ras/MAPK pathways are simultaneously altered, as seen in humans, in a prostate-specific fashion. The double mutants spontaneously develop metastases, which are absent in mice with single pathway alterations. Thus, these mouse models will allow us to establish the role of interactions between the PISK/AKT and Ras/MAPK pathways in the development of metastasis as well as castration resistance and screen for therapeutic agents that can prevent or delay metastatic progression. Our recent studies also identified a novel mechanism of PI3K/AKT activation in response to androgen deprivation therapy, which leads to castration resistant growth. Conversely, PISK inhibition results in enhanced AR transcriptional output. Thus, the compensatory activation of one of these pathways in response to inhibition of the other represents a built-in mechanism of resistance to therapies aimed at targeting either one of these pathways in isolation and suggests that simultaneous inhibition of both the PISK/AKT and AR pathways is necessary to achieve maximal anti-tumor effects and avert castration resistance. Based on this finding, a three-arn phase 2 randomized neoadjuvant pre-prostactomy trial is designed (Aim 2) to target the PISK/AKT and AR pathways alone or in combination and study the downstream signaling and transcriptional output. Associated with this trial, we will also test non-invasive imaging technologies for monitoring pathway alterations and target responses. The success of our proposed research will provide vital insight into and identify therapies for metastasis and castration resistance, two processes that render PCa lethal.